Gamma-delta T lymphocytes represent a minor subpopulation of T cells which are found only in small numbers in peripheral lymphoid organs, but which represent the predominant T cells in may epithelial sites. Although the overall structure of the gamma-delta T cell receptor (TCR) appears to resemble that of the alpha-beta TCR, very little is known about the nature of the antigen and the presentation molecules recognized by the gamma- delta TCR. Although both alpha-beta and gamma-delta T cells are derived from precursors that enter the thymus, gamma-delta T cells appear in the thymus on day 14-15 of gestation, 2-3 days before the appearance of alpha- beta T cells. To further explore the possible contribution of gamma-delta T cells to thymocyte development , we transferred gamma-delta T cells to SCID mice which lack T or B cells. Transfer of gamma-delta T cells resulted in the appearance of CD3-CD4+CD8+ thymocytes. These results suggest that one role of gamma-delta T cells is to promote the development of CD4 and CD8 expression on precursor cells in the thymus. Our studies on thymocyte development have been expanded to elucidate the pathogenesis of autoimmune disease which is observed when mice are thymectomized on day 3 of life. We have demonstrated that the lymph nodes of 3 day old mice contain 20-50% CD4+CD8+HSA+ T cells which express low to intermediate levels of CD3. These double positive T cells are thymus derived and cannot be detected after day 10 of life. These studies suggest that the thymus normally prematurely exports cells to peripheral lymphoid tissue and that removal of the thymus leads to the uncontrolled differentiation of these cells in the periphery which may result in autoimmune disease. Our previous studies had suggested that members of the integrin family of cell surface antigens play an important role in the activation of gamma-delta T cells in vitro. To further investigate the contribution of the integrins to thymocyte development, we analyzed human thymocytes for expression of integrin receptors as well as their ability to adhere to extracellular matrix proteins. A subpopulation of CD4+CD8+ TCR(low) human thymocytes was shown to spontaneously adhere to fibronectin and to express high levels of the fibronectin binding integrins alpha4beta1 and alpha5beta1; however, their adherence to fibronectin could only be inhibited by anti-alpha4beta1 antibodies. Fibronectin non-adherent thymocytes expressed lower levels of CD4/CD8 and higher levels of CD3, but levels of alpha4beta1 and alpha5beta1 identical to the fibronectin adherent population. These studies raise the possibility that activation and deactivation of integrin function may play an important role in thymocyte development.